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Emi1 preferentially inhibits ubiquitin chain elongation by the anaphase-promoting complex

Weiping Wang1, Marc W Kirschner

  • 1Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.

Nature Cell Biology
|May 28, 2013
PubMed

Insights

Emi1 protein inhibits the anaphase-promoting complex (APC) by blocking ubiquitin chain extension on substrates. This study reveals Emi1’s dual inhibition mechanism, stabilizing cell cycle regulators.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The anaphase-promoting complex (APC) is a key ubiquitin ligase regulating the cell cycle.
  • Emi1 is a known APC modulator, often considered a pseudosubstrate inhibitor.

Purpose of the Study:

  • To elucidate the precise mechanism by which Emi1 modulates APC activity.
  • To investigate the role of Emi1’s domains in inhibiting APC-mediated ubiquitylation.

Main Methods:

  • In vitro ubiquitylation assays.
  • Kinetic analysis of APC substrate modification.
  • Domain-specific analysis of Emi1 function.

Main Results:

  • Emi1 inhibits APC activity through dual mechanisms: suppressing substrate binding and ubiquitin transfer.
  • Emi1’s zinc-binding region permits monoubiquitylation but inhibits ubiquitin chain elongation by UBCH10.
  • Emi1’s C-terminal tail blocks Ube2S binding to the APC cullin, further preventing chain elongation.
  • These actions collectively stabilize APC substrates by suppressing ubiquitin chain extension.

Conclusions:

  • Emi1 employs a sophisticated, multi-step inhibition strategy targeting ubiquitin chain elongation on APC substrates.
  • APC substrate degradation is finely tuned by controlling ubiquitin chain extension, a step sensitive to Emi1 inhibition.
  • This provides the first kinetic evidence for Emi1’s mechanism of inhibiting ubiquitin chain elongation.

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